Key roles identified in rodent studies include:
Promotes neurite extension in dorsal root ganglion (DRG) neurons in vitro .
Upregulated in injured sciatic nerves post-transection, correlating with Wallerian degeneration and regeneration phases .
Binds Unc5B receptors to guide axon pathfinding during development .
Modulates excitatory synapses via interactions with latrophilin-3 (LPHN3) .
Induces mechanical allodynia when administered intrathecally in rats .
Enhances GluN2B phosphorylation in spinal cord neurons, amplifying NMDA receptor activity .
Studies using recombinant FLRT3 in rat models reveal its role in pain sensitization:
Neuronal Activation: FLRT3 increases c-Fos expression in spinal cord laminae I–V, indicating broad neuronal excitation .
Receptor Interactions: Binds Unc5B and FGFRs to modulate FGF signaling and axon guidance .
Synaptic Plasticity: Enhances GluN2B phosphorylation, linking FLRT3 to NMDA receptor-dependent pain pathways .
FLRT3 functions in cell-cell adhesion, cell migration, and axon guidance, exhibiting attractive or repulsive effects depending on interacting partners. It plays a role in brain neuron spatial organization, retinal vascular development, and cell-cell adhesion via interactions with ADGRL3 and potentially other latrophilins on adjacent cell surfaces. Interaction with the ROBO1 intracellular domain mediates axon attraction towards NTN1-expressing cells. Conversely, interaction with UNC5B (and possibly other UNC-5 family members) mediates axon growth cone collapse and exerts a repulsive role in neuron guidance. It promotes (in vitro) neurite outgrowth and mediates cell-cell contacts, increasing both neurite number and length. FLRT3 also regulates glutamatergic synapse density and participates in fibroblast growth factor signaling cascades. It's essential for normal embryonic morphogenesis, but not embryonic patterning. Specifically, it's required for normal ventral closure, headfold fusion, definitive endoderm migration, normal basement membrane formation, and anterior visceral endoderm maintenance during embryonic development.